Prostate cancer develops through malignant transformation of the prostate epithelium in a stepwise, mutation-driven process. Although activator protein-1 transcription factors such as JUN have been implicated as potential oncogenic drivers, the molecular programs contributing to prostate cancer progression are not fully understood.
We analyzed JUN expression in clinical prostate cancer samples across different stages and investigated its functional role in a Pten-deficient mouse model. We performed histopathological examinations, transcriptomic analyses and explored the senescence-associated secretory phenotype in the tumor microenvironment.
Elevated JUN levels characterized early-stage prostate cancer and predicted improved survival in human and murine samples. Immune-phenotyping of Pten-deficient prostates revealed high accumulation of tumor-infiltrating leukocytes, particularly innate immune cells, neutrophils and macrophages as well as high levels of STAT3 activation and IL-1β production. Jun depletion in a Pten-deficient background prevented immune cell attraction which was accompanied by significant reduction of active STAT3 and IL-1β and accelerated prostate tumor growth. Comparative transcriptome profiling of prostate epithelial cells revealed a senescence-associated gene signature, upregulation of pro-inflammatory processes involved in immune cell attraction and of chemokines such as IL-1β, TNF-α, CCL3 and CCL8 in Pten-deficient prostates. Strikingly, JUN depletion reversed both the senescence-associated secretory phenotype and senescence-associated immune cell infiltration but had no impact on cell cycle arrest. As a result, JUN depletion in Pten-deficient prostates interfered with the senescence-associated immune clearance and accelerated tumor growth.
Our results suggest that JUN acts as tumor-suppressor and decelerates the progression of prostate cancer by transcriptional regulation of senescence- and inflammation-associated genes. This study opens avenues for novel treatment strategies that could impede disease progression and improve patient outcomes.
Molecular cancer. 2024 May 29*** epublish ***
Torben Redmer, Martin Raigel, Christina Sternberg, Roman Ziegler, Clara Probst, Desiree Lindner, Astrid Aufinger, Tanja Limberger, Karolina Trachtova, Petra Kodajova, Sandra Högler, Michaela Schlederer, Stefan Stoiber, Monika Oberhuber, Marco Bolis, Heidi A Neubauer, Sara Miranda, Martina Tomberger, Nora S Harbusch, Ines Garces de Los Fayos Alonso, Felix Sternberg, Richard Moriggl, Jean-Philippe Theurillat, Boris Tichy, Vojtech Bystry, Jenny L Persson, Stephan Mathas, Fritz Aberger, Birgit Strobl, Sarka Pospisilova, Olaf Merkel, Gerda Egger, Sabine Lagger, Lukas Kenner
Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, 1210, Austria. ., Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, 1210, Austria., Department of Pathology, Medical University of Vienna, Vienna, 1090, Austria., Center for Biomarker Research in Medicine, CBmed GmbH, Graz, 8010, Austria., Institute of Oncology Research, Bellinzona and Faculty of Biomedical Sciences, USI, Lugano, 6500, TI, Switzerland., Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, 1210, Austria., Institute of Physiology, Pathophysiology and Biophysics, University of Veterinary Medicine Vienna, Vienna, 1210, Austria., Department of Biosciences and Medical Biology, Cancer Cluster Salzburg, Paris-Lodron University of Salzburg, Salzburg, 5020, Austria., CEITEC-Central European Institute of Technology, Masaryk University, Brno, 625 00, Czech Republic., Department of Molecular Biology, Umeå University, Umeå, 901 87, Sweden., Charité-Universitätsmedizin Berlin, Hematology, Oncology and Tumor Immunology, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, 10117, Germany., Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, 1210, Austria. ., Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, 1210, Austria. .